Multilocus sequence typing of pathogenic treponemes isolated from contagious ovine digital dermatitis stage five lesions: Implications for disease transmission dynamics.

Contagious ovine digital dermatitis (CODD) causes a severe, infectious foot disease and lameness of sheep, is common within the UK and is now also emerging in other countries. As well as causing severe animal welfare issues, huge economic losses emerge from the disease due to weight loss/lack of weight gain, and veterinary treatments. CODD lesion progress is measured, with a scoring system from 1 (early lesions) to 5 (healed). Here, using samples from an experimental flock infected by natural means, samples were taken from CODD stage 5 lesions, post treatment, and subjected to bacterial isolation and MLST using previously published methods. Sequences were compared to others from the same flock, and those from previous studies. All CODD 5 lesions produced viable Treponema spp. bacteria. High levels of variation of bacteria were seen, with 12 sequence types (STs) for T. medium phylogroup (11 new), 15 STs for T. phagedenis phylogroup (9 new) and six T. pedis STs, of which two were new. This study shows that CODD stage 5 lesions still contain viable bacteria, representing all three known pathogenic Treponema spp. phylogroups, and these may thus play a role in disease transmission and epidemiology despite appearing healed after treatment. The high level CODD treponeme variability within an infected flock where sheep were bought from different sources, as might occur in common agricultural practice, may suggest reasons as to why the bacterial disease is difficult to treat, control and eradicate, and adds further complexity to the polybacterial pathogenesis of these lesions.

Characterising recovery following abdominal aortic aneurysm repair using cardiopulmonary exercise testing and patient reported outcome measures.

PURPOSE: Surgery is associated with a post-operative stress response, changes in cardiopulmonary reserve, and metabolic demand. Here recovery after abdominal aortic aneurysm repair is investigated using cardiopulmonary exercise testing and patient-reported questionnaires. MATERIALS AND METHODS: Patients undergoing open (n = 21) or endovascular (n = 21) repair undertook cardiopulmonary exercise tests, activity, and health score questionnaires pre-operatively and, 8 and 16 weeks, post-operatively. Oxygen uptake and ventilatory parameters were measured, and routine blood tests were undertaken. RESULTS: Recovery was characterised by falls in anaerobic threshold, peak oxygen uptake, and oxygen pulse at 8 weeks which appeared to be associated with operative severity; the fall in peak oxygen uptake was greater following open vs. endovascular repair (3.5 vs. 1.6 ml.kg-1.min-1) and anaerobic threshold showed a similar tendency (3.1 vs. 1.7 ml.kg-1.min-1). In the smaller number of patients re-tested these changes resolved by 16 weeks. Reported health and activity did not change. CONCLUSIONS: Aortic repair is associated with falls in the anaerobic threshold, peak oxygen uptake, and oxygen pulse of a magnitude that reflects operative severity and appears to resolve by 16 weeks. Thus, post-operatively patients may be at higher risk of further metabolic insult e.g. infection. This further characterises physiological recovery from aortic surgery and may assist in defining post-operative shielding time.IMPLICATIONS FOR REHABILITATIONAbdominal aortic aneurysm repair is a life-saving operation, the outcome from which is influenced by pre-operative cardiopulmonary reserve; individuals with poor reserve being at greater risk of peri-operative complications and death. However, for this operation, the physiological impact of surgery has not been studied.In a relatively small sample, this study suggests that AAA repair is associated with a significant decline in cardiopulmonary reserve when measured 8 weeks post-operatively and appears to recover by 16 weeks. Moreover, the impact may be greater in endovascular vs. open repair.

The dysbiosis of ovine foot microbiome during the development and treatment of contagious ovine digital dermatitis.

BACKGROUND: Contagious Ovine Digital Dermatitis (CODD) is an emerging and common infectious foot disease of sheep which causes severe welfare and economic problems for the sheep industry. The aetiology of the disease is not fully understood and control of the disease is problematic. The aim of this study was to investigate the polybacterial aetiopathogenesis of CODD and the effects of antibiotic treatment, in a longitudinal study of an experimentally induced disease outbreak using a 16S rRNA gene amplicon sequencing approach. RESULTS: CODD was induced in 15/30 experimental sheep. During the development of CODD three distinct phenotypic lesion stages were observed. These were an initial interdigital dermatitis (ID) lesion, followed by a footrot (FR) lesion, then finally a CODD lesion. Distinct microbiota were observed for each lesion in terms of microbial diversity, clustering and composition. Porphyromonadaceae, Family XI, Veillonellaceae and Fusobacteriaceae were significantly associated with the diseased feet. Veillonellaceae and Fusobacteriaceae were most associated with the earlier stages of ID and footrot rather than CODD. Following antibiotic treatment of the sheep, the foot microbiota showed a strong tendency to return to the composition of the healthy state. The microbiota composition of CODD lesions collected by swab and biopsy methods were different. In particular, the Spirochaetaceae family were more abundant in samples collected by the biopsy method, suggesting that these bacteria are present in deeper tissues of the diseased foot. CONCLUSION: In this study, CODD presented as part of a spectrum of poly-bacterial foot disease strongly associated with bacterial families Porphyromonadaceae, Family XI (a family in Clostridiales also known as Clostridium cluster XI), Veillonellaceae and Fusobacteriaceae which are predominately Gram-negative anaerobes. Following antibiotic treatment, the microbiome showed a strong tendency to return to the composition of the healthy state. The composition of the healthy foot microbiome does not influence susceptibility to CODD. Based on the data presented here and that CODD appears to be the severest end stage of sheep infectious foot disease lesions, better control of the initial ID and FR lesions would enable better control of CODD and enable better animal welfare.

Whole-flock, metaphylactic tilmicosin failed to eliminate contagious ovine digital dermatitis and footrot in sheep: a cluster randomised trial.

The aim of this study was to evaluate the clinical success of whole-flock systemic tilmicosin and enhanced biosecurity in eliminating active contagious ovine digital dermatitis (CODD) from sheep flocks. Thirty flocks in the UK were randomly allocated to receive either treatment as usual (as per the farmer's normal routine) or whole-flock treatment with tilmicosin, together with isolation and extended treatment of clinically affected individuals and isolation and treatment of purchased sheep during the study period. All flocks were visited once at onset of the trial to examine all sheep. One year later, all sheep were re-examined to determine the presence/absence of clinical lesions. The primary outcome was the clinical elimination of CODD from flocks. Secondary outcomes were reduction in prevalence of CODD, clinical elimination of footrot and reduction in prevalence of footrot. The analysis included 11 control flocks and 13 intervention flocks, with initially 3460 and 4686 sheep, respectively. For CODD: at follow-up, in the intervention group, 6/13 (46 per cent) flocks had a prevalence of zero compared with 1/11 (9 per cent) in the control group (P=0.12). For footrot: at follow-up, no flocks had a prevalence of zero. Therefore, the intervention is not recommended for the elimination of CODD or footrot in the UK.

Severe Foot Lesions in Dairy Goats Associated with Digital Dermatitis Treponemes.

Treponeme-associated foot disease has been described in cattle with digital dermatitis and sheep with contagious ovine digital dermatitis. In this study, severe foot lesions in dairy goats associated with digital dermatitis treponemes (i.e. Treponema medium, Treponema phagedenis and Treponema pedis) were characterized macroscopically, radiographically and histologically. The main macroscopic foot lesion was of extensive solar ulceration with or without exophytic papilliform hyperkeratosis. Radiographically, the distal phalanx and distal sesamoid bones were severely damaged and remodelled. Histologically, the lesion was categorized as a chronic lymphoplasmacytic, suppurative and ulcerative pododermatitis. Immunohistochemistry identified the spirochaetal microorganisms located extracellularly in the superficial horn. Study limitations mean that the treponeme bacteria could not be considered the sole or causal agents in the cases described.

Histopathological Characterization of the Lesions of Contagious Ovine Digital Dermatitis and Immunolabelling of Treponema-like Organisms.

Contagious ovine digital dermatitis (CODD) is a cause of severe lameness in sheep and the three Treponema phylogroups Treponema medium/Treponema vincentii-like, Treponema phagedenis-like and Treponema pedis have been associated with clinical disease. The aims of this study were: (1) to describe the histopathological changes associated with each previously established grade of clinical lesion, and (2) to investigate immunohistochemically the association of the Treponema-like organisms with the observed histopathological changes. Early lesions were characterized by lymphoplasmacytic infiltration of the distal digital skin, with suppurative coronitis and intracorneal pustules. In more advanced stages of the disease there was complete separation of the dorsal wall of the hoof with a necrotizing and fibrinosuppurative exudate and dermatitis. The later lesions were mostly resolved, but with milder suppurative changes remaining within the cornified layer and periosteal reaction of the dorsal aspect of the distal phalanx. Large numbers of Treponema-like organisms were identified within early grade lesions (as well as later, more advanced grade lesions) and were specifically associated with the observed histopathological changes. The results of this study provide some evidence in support of the hypothesis that the three CODD-associated Treponema phylogroups are involved in the aetiopathogenesis of this disease.

Sheep and farm level factors associated with contagious ovine digital dermatitis: A longitudinal repeated cross-sectional study of sheep on six farms.

Contagious ovine digital dermatitis (CODD) is a cause of severe lameness in sheep in the UK currently affecting approximately 50% of farms. Six farms were studied in North Wales to investigate (1) the prevalence dynamics of CODD, (2) the association between sheep with CODD and potential risk factors and (3) the impact of CODD on lameness in sheep. The farms were visited at approximately two-month intervals between June 2012 and October 2013 and 6515 sheep were examined. The mean sheep level prevalence of CODD varied between farms (2.5-11.9%). Within farms, prevalence may increase in the late summer/early autumn and after housing. Environmental risk factors included larger flocks, lowland pasture, lush pasture and poached pasture. Co-infection of a foot with footrot was strongly associated with CODD in that foot (OR: 7.7 95% CI: 3.9-15.5 P<0.001) but negatively associated with co-infection of a foot with interdigital dermatitis (OR: 0.04 95% CI: 0.02-0.1 P<0.001). Reinfection with CODD was observed in 78 individual sheep but there was no re-infection at foot level. Lameness on all farms reduced during the study and seasonal changes in lameness followed similar patterns to those for CODD. Infection with CODD leads to a greater increase in locomotion score compared to footrot or interdigital dermatitis and CODD lesion grade was strongly associated with being lame. Sheep with CODD in more than one foot were more likely to be lame (OR: 25.0 95% CI: 12.5-49.9 P<0.001) than those with just one foot affected (OR:10.0 95% CI: 8.6-11.6 P<0.001). The biggest risk factor for CODD is co-infection with footrot and therefore control of footrot should help reduce the risk of CODD on affected farms. Furthermore environmental risk factors for CODD are similar to those for footrot adding weight for control strategies that target both diseases in tandem. The routine repeated gathering of sheep for the purposes of treating all lame sheep might be an effective control strategy for lameness on some sheep farms. Effective systemic immunity to CODD in sheep appears to be lacking, as 78 sheep were observed to be re-infected with CODD during the survey. However, there is epidemiological evidence that there may be some local immunity within the foot warranting further investigation.

The gastrointestinal tract as a potential infection reservoir of digital dermatitis-associated treponemes in beef cattle and sheep.

Digital dermatitis (DD) is an important cause of lameness in dairy cattle worldwide. It has now been reported in beef cattle and also sheep (contagious ovine digital dermatitis [CODD]). Three Treponema phylogroups are consistently isolated from lesions, Treponema medium-like, Treponema phagedenis-like, and Treponema pedis. The gastrointestinal (GI) tract and feces are suggested sites of treponemal infection in dairy cattle; however, isolation of DD-associated treponemes from these areas has previously failed. This study surveyed gingival tissues, rectal tissues, and feces of beef cattle and sheep for the molecular presence (PCR) and isolation of the three cultivable DD-treponeme phylogroups. Of the sheep gingival (n = 40) and rectal (n = 40) tissues, 1/40 gingival tissues was positive for DD-associated treponemes (T. pedis), as were 3/40 rectal tissues (one containing T. medium-like and two containing T. pedis). No DD-associated treponeme DNA was amplified from beef cattle rectal tissues (n = 40); however, 4/40 beef gingival tissues were positive for DD-associated treponemes (all containing T. phagedenis-like). A T. phagedenis-like DD-associated treponeme was isolated from the rectal tissue of a CODD symptomatic sheep. Beef cattle (n = 41) and sheep (n = 79) feces failed to amplify DD-associated Treponema DNA. Twenty-two treponemes were isolated from sheep feces; however, upon phylogenetic analysis, these clustered with the considered nonpathogenic treponemes. This study detected DD-associated treponemes in the GI tract tissues of sheep and beef cattle and successfully isolated a DD-associated treponeme from ruminant rectal tissue. This gives evidence that the GI tract is an important infection reservoir of DD-associated treponemes in multiple DD-infected species.

Clinical and radiographic features of contagious ovine digital dermatitis and a novel lesion grading system.

Contagious ovine digital dermatitis (CODD) is an infectious foot disease of sheep causing severe lameness. Diagnosis is currently made using broad anecdotal descriptions. The aim of this study was to systematically and formally describe the clinical presentation of the disease in terms of (1) a lesion grading system; (2) associated radiographic changes and (3) severity of associated lameness. A five-point lesion grading system was developed and applied to 908 sheep affected by CODD from six farms. Sheep with lesions typical of each grade were euthanased and their feet radiographed. Radiographic abnormalities including soft tissue and bony changes were evident in feet with lesions graded 2-5. In order to quantify the welfare impact of CODD, all the 908 sheep were locomotion scored. Five hundred and eighty-five (64.5% (95% CI 61.4% to 67.6%)) were lame. The locomotion score for affected sheep increased with worsening pathological changes. Once healing had begun the locomotion score decreased. In conclusion the five-point grading system may be used to clinically describe stages of CODD lesions. The radiographic changes revealed examples of deeper pathological changes and there was a strong association between the lesion grading system and locomotion score in affected sheep.

A practical tool for locomotion scoring in sheep: reliability when used by veterinary surgeons and sheep farmers.

A four-point locomotion scoring tool for sheep was developed and tested on 10 general practice veterinary surgeons (VS) and 10 sheep farmers. Thirty-four video clips of sheep displaying different locomotion scores were recorded and randomly assorted. Following a set period of training using four other video clips typical of the four locomotion scores, participants then scored the 34 test clips. The participants repeated the training and the exercise one month later. There were high levels of intraobserver repeatability: weighted κ (κW) 0.81 for VS and 0.83 for farmers. There was no difference in intraobserver repeatability between vets and farmers (Wilcoxon signed rank P=0.8). When considering the overall distribution of scores within the video package, there were high levels of interobserver repeatability: mean κW 0.73 for VS and 0.72 for farmers. However, the repeatability for the individual locomotion scores was only fair to moderate. It is therefore recommended that when observations are repeated on different occasions they are made by the same observer.

High-level association of bovine digital dermatitis Treponema spp. with contagious ovine digital dermatitis lesions and presence of Fusobacterium necrophorum and Dichelobacter nodosus.

Contagious ovine digital dermatitis (CODD) is an important foot disease in sheep, with significant animal welfare and economic implications. It is thought that CODD emerged from bovine digital dermatitis (BDD) via treponemal bacteria. With wildlife species such as elk now suffering a CODD-like disease, it is imperative to clarify these disease etiologies. A large investigation into treponemal association with CODD is warranted. CODD lesions (n = 58) and healthy sheep foot tissues (n = 56) were analyzed by PCR for the three BDD-associated Treponema phylogroups and two other lameness-associated bacteria, Dichelobacter nodosus and Fusobacterium necrophorum. Spirochete culture was also attempted on CODD lesions. "Treponema medium/Treponema vincentii-like," "Treponema phagedenis-like," and Treponema pedis spirochetes were identified in 39/58 (67%), 49/58 (85%), and 41/58 (71%) of CODD lesions, respectively. One or more BDD-associated Treponema phylogroups were detected in 100% of CODD lesions. Healthy foot tissues did not amplify BDD-associated Treponema phylogroup DNA. D. nodosus and F. necrophorum were present in 34/58 (59%) and 41/58 (71%) of CODD lesions and 22/56 (39%) and 5/56 (9%) of healthy foot tissues, respectively. Thirty-two spirochetes were isolated from CODD lesions, with representatives clustering with, and indistinguishable from, each of the three BDD-associated Treponema phylogroups based on 16S rRNA gene comparisons. This study for the first time demonstrates a high-level association for BDD treponeme phylogroups in CODD and their absence from healthy tissues, supporting the hypothesis that BDD treponemes play a primary causative role in CODD and confirming that the specific PCR assays are an effective differential diagnostic tool for CODD.

Contagious ovine digital dermatitis: an emerging disease.

The novel sheep disease, contagious ovine digital dermatitis (CODD) was first described in the UK in 1997. The disease is characterised by severe lameness associated with initial inflammation at the coronary band, followed by progressive separation of the hoof capsule from the underlying tissue. On microbiological examination, treponeme bacteria have been frequently isolated from cases of CODD, including treponemes phylogenetically identical to those associated with bovine digital dermatitis (BDD). Dichelobacter nodosus and Fusobacterium necrophorum have also been isolated from CODD lesions although their role in the pathogenesis remains uncertain. While epidemiological data indicate that the prevalence of CODD is increasing in the UK, the routes of transmission and associated risk factors have not been clearly elucidated. Evidenced-based treatment trials indicate that parenteral administration of long-acting amoxicillin is an efficacious treatment for CODD, while anecdotal evidence suggests other antibiotics, given locally and/or parenterally, may also be beneficial. Further microbiological and epidemiological research is urgently required to develop sustainable control strategies, including the development of vaccines and appropriate biosecurity and farm management protocols. In this review current knowledge of the clinical, aetiological, and epidemiological aspects of CODD is assessed as well as approaches to its control.

Presence of digital dermatitis treponemes on cattle and sheep hoof trimming equipment.

Digital dermatitis (DD) is an infectious foot disease causing severe lameness in dairy cattle (worldwide) and sheep (UK). This study investigated whether DD Treponema phylogroups can be present on equipment used to trim ruminant hooves and, therefore, consider this trimming equipment as a possible vector for the transmission of DD. Equipment was tested after being used to trim DD symptomatic and asymptomatic cattle and sheep hooves, and subsequently after disinfection of equipment. After trimming, 'Treponema medium/Treponema vincentii-like', 'Treponema phagedenis-like' and 'Treponema denticola/T putidum-like' DD spirochaetes, were shown to be present on 23/37 (62%), 21/37 (57%) and 20/37 (54%) of knives, respectively. After disinfection, detection rates for the DD treponemes were 9/37 (24%), 6/37 (16%) and 3/37 (8%), respectively. Following culture of a swab, an isolate belonging to the T phagedenis-like spirochaetes was identified from a knife sample after trimming a DD positive cow. No isolates were obtained from knife samples after disinfection. This new data has, for the first time, identified treponemes in the farm environment, and highlighted disinfection of hoof trimming equipment between animals and between farms, as a logical precaution to limit the spread of DD.

Farmer reported prevalence and factors associated with contagious ovine digital dermatitis in Wales: A questionnaire of 511 sheep farmers.

In 2012, 2000 questionnaires were sent to a random sample of Welsh sheep farmers. The questionnaire investigated farmers' knowledge and views on contagious ovine digital dermatitis (CODD) - an emerging disease of sheep responsible for causing severe lameness, welfare and production problems. The overall response rate was 28.3% with a usable response rate of 25.6%. The between farm prevalence of CODD was 35.0% and the median farmer estimated prevalence of CODD was 2.0%. The disease now appears endemic and widespread in Wales. Furthermore, there has been a rapid increase in reports of CODD arriving on farms since the year 2000. Risk factors for CODD identified in this study include the presence of bovine digital dermatitis (BDD) in cattle on the farm and larger flocks. Farmers also consider concurrent footrot/interdigital dermatitis, buying in sheep, adult sheep, time of year and housing to be associated with CODD. Further experimental research is necessary to establish whether these observations are true associations.

Successful correction of D-lactic acid neurotoxicity (drunken lamb syndrome) by bolus administration of oral sodium bicarbonate.

Drunken lamb syndrome (DLS) has recently been described as lamb D-lactic acidosis syndrome (LDLAS). In 2012, 18 lambs aged between 7 days and 28 days with LDLAS were identified. Biochemically, each lamb had a metabolic acidosis characterised by D-lactic acidosis and exhibited clinical signs including: not hyperthermic, no evidence of dehydration, demonstrating an ataxic gait tending to recumbency (DLS) and possibly somnolence. These lambs received 50 mmol of sodium bicarbonate as an 8.4 per cent solution given orally, together with parenteral long-acting amoxicillin. All 18 cases made a full clinical recovery. This study demonstrates a novel effective treatment for a disease that is usually fatal, and also demonstrates a strong correlation between venous plasma bicarbonate concentrations and venous plasma D-lactate concentrations (R(2)=0.49).

A prospective on farm cohort study investigating the epidemiology and pathophysiology of drunken lamb syndrome.

Drunken lamb syndrome (DLS) is a fatal disease of unknown aetiology affecting young lambs. In 2011, a prospective on farm cohort study was carried out to investigate the epidemiology and pathophysiology of DLS. Ten cases from a cohort of 1635 crossbred and pure Welsh Mountain lambs were identified as having DLS on the basis of characteristic clinical signs. Renal histopathology demonstrated nephrosis in all 10 cases. Some cases also demonstrated concurrent intestinal pathology. The cases were significantly smaller than the cohort, nine out of the 10 were twins, and they all demonstrated a severe metabolic acidosis characterised by elevated D-lactate. This study demonstrates that D-lactate--probably initiated by the overgrowth of intestinal microorganisms--appears to be the cause of the metabolic acidosis seen in cases of DLS, and to be responsible for the clinical signs seen. It is unclear as to the significance of the nephrosis lesions, and the name 'Lamb Nephrosis' may be misleading. Treatment may be possible using solutions of sodium bicarbonate.

Improvement of bone disease by imiglucerase (Cerezyme) therapy in patients with skeletal manifestations of type 1 Gaucher disease: results of a 48-month longitudinal cohort study.

Progressive skeletal disease accounts for some of the most debilitating complications of type 1 Gaucher disease. In this 48-month, prospective, non-randomized, open-label study of the effect of enzyme replacement therapy on bone response, 33 imiglucerase-naïve patients (median age 43 years with one or more skeletal manifestations such as osteopenia, history of bone crisis, or other documented bone pathology) received imiglucerase 60 U/kg/2 weeks. Substantial improvements were observed in bone pain (BP), bone crises (BC), and bone mineral density (BMD). Improvements in BP were observed at 3 months (p < 0.001 vs baseline) and continued progressively throughout the study, with 39% of patients reporting pain at 48 months vs 73% at baseline. Eleven of the 13 patients with a pre-treatment history of BC had no recurrences. Biochemical markers for bone formation increased; markers for bone resorption decreased. Steady improvement of spine and femoral neck BMD, measured using dual-energy X-ray absorptiometry was noted. Mean Z score for spine increased from -0.72 +/- 1.302 at baseline to near-normal levels (-0.09 +/- 1.503) by month 48 (p = 0.042) and for femoral neck from -0.59 +/- 1.352 to -0.17 +/- 1.206 (p = 0.035) at month 36. This increase was sustained at 48 months. With imiglucerase treatment, patients should anticipate resolution of BC, rapid improvement in BP, increases in BMD, and decreased skeletal complications.

Imiglucerase (Cerezyme) improves quality of life in patients with skeletal manifestations of Gaucher disease.

Health-related quality of life (HRQOL) can be diminished in patients with type 1 Gaucher disease (GD) owing to the debilitating clinical manifestations of this chronic disease. This study investigates the impact of imiglucerase treatment on HRQOL of patients with type 1 GD and bone involvement. Thirty-two previously untreated type 1 GD patients with skeletal manifestations including bone pain, medullary infarctions, avascular necrosis, and lytic lesions received biweekly imiglucerase (at 60 U/kg). The Short Form-36 Health Survey (SF-36) was administered at regular intervals to assess HRQOL. Mean baseline SF-36 physical component summary (PCS) scores were diminished relative to US general population norms. Low PCS scores were more common in patients with medullary infarction, lytic lesions, and higher bone pain severity scores. Statistically significant improvements were observed for all eight SF-36 subscales after 2 years of treatment. Mean PCS and mental component summary (MCS) scores increased to within the normal range after 2 years of treatment and were maintained through year 4. Large HRQOL gains were observed even in patients with the most advanced disease and lowest baseline PCS scores. Imiglucerase treatment has a significant positive impact on HRQOL of type 1 GD patients with skeletal disease, including those with bone infarctions, lytic lesions, and avascular necrosis.